Right ventricular maladaptive functional and electrical remodeling in male Fischer rats during progressive pulmonary arterial hypertension

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Cardiac arrhythmias are suspected as a major cause of sudden cardiac death (SCD) in pulmonary arterial hypertension (PAH); however, the mechanisms underlying right ventricle (RV) electrical remodeling, arrhythmias, and SCD in PAH remain unclear. We investigated the mechanisms of increased susceptibility to SCD during progressive PAH in Fischer CDF rat monocrotaline (MCT) model. Echocardiography, electrocardiogram, and cardiac catheterization were performed 4- and 5-weeks post-MCT injection (MCT-4 and MCT-5 groups, respectively). Hearts were isolated and Langendorff perfused, and changes in action potential (AP) duration (APD) were evaluated by voltage optical mapping. A progressive increase in RV systolic pressure was observed in MCT-4 and MCT-5 compared to controls. In MCT-4, we observed RV hypertrophy with preserved cardiac function and chamber size, indicating adaptive RV remodeling. Conversely, maladaptive RV remodeling was seen in MCT-5, indicated by reduced cardiac function, along with the increased RV internal diameter. Electrically, we observed delayed repolarization and prolongation of RV AP and QT interval in the MCT-5 compared to controls and MCT-4. Electrical changes were consistent with decreased Kcnh2, Kcnk2 and Scn7a expression in the RV. Reduced RV vascular density together with up-regulation of hypoxia regulated gene were noted in MCT-5 compared to controls, which along with the observed ST elevation suggests RV ischemia. Together, Fischer rats develop mal-adaptive RV functional and electrical remodeling at 5 weeks post-MCT that is associated with reduced RV potassium and sodium channel expression and elevated markers of RV ischemia. These changes may contribute to increased susceptibility to arrhythmias and SCD in PAH.